Chemotherapeutic methods, often in combination with alternative forms of treatment such as radiation therapy, provide the best hope for treatment of many forms of cancer and other conditions of unwanted cellular growth. Cancers that comprise solid tumors, either malignant or benign, are often treated with chemotherapeutic methods. This is also true for conditions that are not well-suited for treatment by surgical methods, such as malignant cancers and cancers that are not characterized by the formation and growth of tumors. Conditions classified as hematological malignancies are commonly treated using chemotherapeutic methods. Specific types of hematological malignancies include leukemia, lymphoma, and multiple myeloma. Specific types of solid tumors include thyroid cancer, breast cancer, prostate cancer, and others. Unfortunately, cures are not yet available for many cases of hematological malignancies and solid tumors; treatment often focuses instead on containment of the disease and improvement of the patient's quality of life.
For example, multiple myeloma (MM) embodies a plasma cell disorder characterized by clonal neoplastic proliferation of plasma cells engaged in the production of a monoclonal immunoglobulin, usually monoclonal IgG or IgA. MM accounts for 1% of all malignant disease and slightly more than 10% of all hematologic malignancies, with over 15,000 new cases of the disease diagnosed in the United States in 2005.
A variety of methods have been developed for treating myeloma. For example, U.S. Pat. No. 7,094,885 describes a method of treating conditions that arise in or near bone such as myeloma, with compositions having as their active ingredient a radionuclide complexed with a chelating agent such as macrocyclic aminophosphonic acid.
U.S. Pat. No. 6,992,207 describes alkylating di- and tripeptides based on a melphalan unit, and one or two additional amino acids or amino acid derivatives, which can be used in the treatment of carcinogenic diseases such as myeloma.
U.S. Pat. No. 6,986,891 describes a method of killing or inhibiting the growth of myeloma tumor cells or ovarian cancer tumor cells comprising administering to an individual in need thereof a composition comprising a monoclonal antibody.
U.S. Pat. No. 6,884,804 describes compounds that are inhibitors of protein kinase, particularly inhibitors of Src mammalian protein kinase involved in cell proliferation, cell death and response to extracellular stimuli. Pharmaceutical compositions comprising the inhibitors are used in the treatment and prevention of various disorders including myeloma.
U.S. Pat. No. 6,492,333 describes the identification and use of compositions for treating myeloma bone disease. The compositions inhibit proteasomal activity and decrease the activity of the transcription factor NF-kB. Assessment of a candidate compound for its ability to inhibit production or activity of proteasomal enzymes or NF-kB is explored as a means to identify agents to treat myeloma bone disease.
Therapy for MM includes induction, maintenance, and supportive aspects. The induction portion of the treatment aims at reducing the volume of diseased plasma cells and achieving a plateau phase. Different drugs and treatment modalities, including bone marrow transplantation, are under investigation, and MM remains a subject of research in the medical profession. Nevertheless, most patients having MM succumb to the disease within 36-48 months from the time of diagnosis. The limitations of effective therapy for MM are primarily associated with a low cell proliferation rate and multi-drug resistance.
An ideal chemotherapy-based method of treatment of cancers such as hematological malignancies would be effective on a variety of tumor cell lines. An ideal chemotherapeutic agent for such methods would be readily available and/or easily prepared, and would not interfere with (or, better still, would be synergistic with) other chemotherapeutic treatments that may be administered concurrently. The ideal chemotherapeutic candidate compound would effectively treat tumor cells at concentrations that are not toxic to healthy cells. In addition, the ideal method of treatment would effectively treat tumor cells with minimal administrations of the active agent(s). Using these ideal characteristics as a guide, the present disclosure provides compositions and methods of treatment of cancer that are directed at addressing one or more of the abovementioned limitations, as well as related issues in the fields of medicine and medicinal chemistry.